The pathological events underlying degeneration of select populations of neurons during the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain unknown. We have demonstrated that the neurons of the nucleus basalis subfield of the cholinergic basal forebrain (CBF) display phenotypic differences in their expression of chemical markers in people with no cognitive impairment (NCI) and MCI. For example, the number of CBF neurons displaying choline acetyltransferase (CHAT) and vesicular acetylcholine transporter immunoreactivity are preserved (39), whereas CBF neurons containing the protein and gene for the high affinity (trkA) signal transduction NGF receptor are significantly reduced in MCI (17,82). These observations suggest that alterations in neurotrophins are an early marker for dementia. Interestingly, ChAT activity remains stable in the cortex of MCI individuals (24,28), suggesting that cholinergic synthesis is still functional within neurons of the CBF in these people. In contrast, it is not known whether cortical trkA levels are reduced in MCI as they are in end stage AD (58,83). If trkA levels remain stable in the cortex of MCI people, this would suggest that non-CBF trkA receptor positive cells, such as glial cells in the cortex, are compensating for the reduction in the production of this receptor seen in CBF neurons of people with MCI. In addition to trkA, other NGF-related proteins may contribute to the vulnerability of CBF neurons in the progression of dementia. Interestingly, we have found a reduction in the number of NGFrelated Nur77 containing CBF neurons as well as impaired synthesis of Nur77 in CBF neurons in people with MCI and a further reduction in AD. This is in contrast to our finding that the reduction of trkA positive CBF neurons is not accelerated in AD as compared to MCI (17,82). Therefore, Specific Aim 2 will test the hypothesis that the number of CBF Nur77 immunopositive neurons are reduced in people with MCI and that the loss is exacerbated in AD. Moreover, we will examine whether the synthesis of Nur77 is reduced in people with MCI. Another candidate associated with CBF degeneration is the microtubuleassociated protein tau, which accumulates to form neurofibrillary tangles (NFTs). CBF neurons are invested with NFTs in preclinical AD (94, 102). Thus, a common hypothesis is that accumulation of tau into NFTs results in cellular protein and gene dysfunction and ultimately cell death (43,44,115). The effect that the accumulation of tau has on the genetic signature of individual CBF neurons in MCI and whether it differs from AD is not known. Specific Aim 3 will test the hypothesis that there is a selective downregulation of classes of gene transcripts in CBF NFT versus non-NFT neurons during the transition from NCI to MCI. These studies will provide data to devise effective pharmacogenetic therapies.